Department of Life Science, Faculty of Medicine, Shimane University, Shimane 690‑0823, Japan.
Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104‑0045, Japan.
Int J Oncol. 2021 Mar;58(3):397-408. doi: 10.3892/ijo.2021.5173. Epub 2021 Jan 21.
A synthetic peptide that blocks the interaction between the metastasis‑enhancing calcium‑binding protein, S100A4, and its effector protein, methionine aminopeptidase 2 (MetAP2) (the NBD peptide), was previously demonstrated to inhibit the angiogenesis of endothelial cells, leading to the regression of human prostate cancer in a xenograft model. However, the effects of the NBD peptide on the malignant properties of cancer cells that express S100A4 remain to be elucidated. The present study demonstrates that the NBD peptide inhibits the invasiveness and metastasis of highly metastatic human mammary carcinoma cells. The introduction of the peptide into MDA‑MB‑231 variant cells resulted in the suppression of matrix degradation in a gelatin invadopodia assay and invasiveness in a Matrigel invasion assay. In line with these results, the peptide significantly downregulated the expression of matrix metalloproteinase (MMP)‑14 (MT1‑MMP). Mechanistic analysis of the downregulation of MMP‑14 revealed the suppression of the expression of the transcription factor, specificity protein 1 (Sp1), but not that of nuclear factor (NF)‑κB, early growth response 1 (EGR1) or ELK3, all of which were reported to be involved in transcriptional regulation of the MMP‑14 gene. At the same time, evidence suggested that the NBD peptide also suppressed Sp1 and MMP‑14 expression levels in MDA‑MB‑468 cells. Importantly, the intravenous administration of the NBD peptide encapsulated in liposomes inhibited pulmonary metastasis from mammary gland tumors in mice with xenograft tumors. These results indicate that the NBD peptide can suppress malignant tumor growth through the suppression of the Sp1/MMP‑14 axis. Taken together, these results reveal that the NBD peptide acts on not only endothelial cells, but also on tumor cells in an integrated manner, suggesting that the peptide may prove to be a promising cancer therapeutic peptide drug.
一种合成肽可阻断转移增强钙结合蛋白 S100A4 与其效应蛋白蛋氨酸氨肽酶 2（MetAP2）（NBD 肽）之间的相互作用，先前的研究表明，该肽可抑制内皮细胞的血管生成，从而导致异种移植模型中人类前列腺癌的消退。然而，NBD 肽对表达 S100A4 的癌细胞恶性特性的影响仍有待阐明。本研究表明，NBD 肽可抑制高度转移性人乳腺癌细胞的侵袭和转移。将该肽引入 MDA-MB-231 变体细胞中，导致明胶侵袭足突分析中的基质降解和 Matrigel 侵袭分析中的侵袭受到抑制。与这些结果一致，该肽显著下调了基质金属蛋白酶（MMP）-14（MT1-MMP）的表达。MMP-14 下调的机制分析表明转录因子特异性蛋白 1（Sp1）的表达受到抑制，但核因子（NF）-κB、早期生长反应 1（EGR1）或 Elk3 的表达不受抑制，所有这些因子均被报道参与 MMP-14 基因的转录调控。同时，有证据表明，NBD 肽也可抑制 MDA-MB-468 细胞中的 Sp1 和 MMP-14 表达水平。重要的是，包封在脂质体中的 NBD 肽的静脉给药抑制了异种移植肿瘤小鼠乳腺肿瘤的肺转移。这些结果表明，NBD 肽可通过抑制 Sp1/MMP-14 轴来抑制恶性肿瘤的生长。综上所述，这些结果表明，NBD 肽不仅可以作用于内皮细胞，还可以综合作用于肿瘤细胞，提示该肽可能成为一种有前途的癌症治疗肽类药物。
